The aryl hydrocarbon receptor: a perspective on potential roles in the immune system

Abstract

The aryl hydrocarbon receptor (AHR) is a protein best known for its role in mediating toxicity. Over 30 years of research has uncovered additional roles for the AHR in xenobiotic metabolism and normal vascular development. Activation of the AHR has long been known to cause immunotoxicity, including thymic involution. Recent data suggesting a role for the AHR in regulatory T-cell (Treg) and T-helper 17 (Th17) cell development have only added to the excitement about this biology. In this review, we will attempt to illustrate what is currently known about AHR biology in the hope that data from fields as diverse as evolutionary biology and pharmacology will help elucidate the mechanism by which AHR modifies immune responses. We also will discuss the complexities of AHR pharmacology and genetics that may influence future studies of AHR in the immune system.

Figure 1

Protein domains found in the aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT). The nuclear localization sequence (NLS) and nuclear export sequence (NES) are found within the basic helix loop helix (bHLH) region. The bHLH also plays a critical role in DNA binding. The characteristic domains in Per-ARNT-Sim (PAS) family members mediate heterodimerization and chaperone binding. The C-terminus is variable, but contains the transactivation domain (TAD) responsible for activating transcription after DNA binding.

Figure 2

The aryl hydrocarbon receptor (AHR) signalling pathway. Hydrophobic ligands enter the cell via diffusion through the cell membrane. Ligands bind to the AHR in the cytosol. Ligand binding causes conformational changes leading to nuclear localization sequence (NLS) exposure and the AHR complex translocates to the nucleus. In the nucleus, the AHR binds its heterodimeric partner, the aryl hydrocarbon receptor nuclear translocator (ARNT) and directs transcription from dioxin response elements (DREs), upstream of target genes. Signalling through the AHR is down-regulated by two means, the proteasome and a feed-back pathway involving the aryl hydrocarbon receptor repressor (AHRR). The AHRR is an AHR gene target and its expression is up-regulated by AHR signalling. Signalling by the AHR leads to three biological pathways referred to as the adaptive metabolic pathway, the toxic pathway, and the developmental pathway. ARA9, aryl hydrocarbon receptor associated 9; Hsp90, heat shock protein 90.